These studies are designed to investigate the significance of the various signals which impinge upon the liver and determine hepatic glucose balance. We have shown that glucose, rather than insulin, is the major determinant of glucose uptake by the isolated, blood perfused liver. Computer simulation predicts that our results can be explained if glucose, rather than insulin, is the primary determinant of glycogen synthetase activity in the liver. Proposed studies include observing the dynamic changes in synthetase and phosphorylase activity and glycogen synthesis provoked by glucose and insulin. In a second series of studies, we plan to investigate the effects of glucose and insulin on liver carbohydrate metabolism which are mediated via the central nervous system. We have introduced a new cross-perfusion technique which allows us to vary the insulin and glucose concentrations at the hypothalamus independent of the concentrations perfusing the liver. By the use of appropriate blocking agents the neural mechanisms involved in the direct control of hepatic glucose balance by the hypothalamus will be investigated.